title: The role of gap junction communication and oxidative stress in the propagation of toxic effects among high-dose α-particle-irradiated human cells.
abstract: We investigated the roles of gap junction communication and oxidative stress in modulating potentially lethal damage repair in human fibroblast cultures exposed to doses of α particles or γ rays that targeted all cells in the cultures. As expected, α particles were more effective than γ rays at inducing cell killing; further, holding γ-irradiated cells in the confluent state for several hours after irradiation promoted increased survival and decreased chromosomal damage. However, maintaining α-particle-irradiated cells in the confluent state for various times prior to subculture resulted in increased rather than decreased lethality and was associated with persistent DNA damage and increased protein oxidation and lipid peroxidation. Inhibiting gap junction communication with 18-α-glycyrrhetinic acid or by knockdown of connexin43, a constitutive protein of junctional channels in these cells, protected against the toxic effects in α-particle-irradiated cell cultures during confluent holding. Upregulation of antioxidant defense by ectopic overexpression of glutathione peroxidase protected against cell killing by α particles when cells were analyzed shortly after exposure. However, it did not attenuate the decrease in survival during confluent holding. Together, these findings indicate that the damaging effect of α particles results in oxidative stress, and the toxic effects in the hours after irradiation are amplified by intercellular communication, but the communicated molecule(s) is unlikely to be a substrate of glutathione peroxidase.
authors.affiliation: Department of Radiology, UMDNJ-New Jersey Medical School Cancer Center, Newark, New Jersey 07103, USA.
authors.forename: Narongchai
authors.initials: N
authors.lastname: Autsavapromporn
authors.forename: Sonia M
authors.initials: SM
authors.lastname: de Toledo
authors.forename: John B
authors.initials: JB
authors.lastname: Little
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Jay-Gerin
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Harris
authors.forename: Edouard I
authors.initials: EI
authors.lastname: Azzam
mesh_terms: D000512:Alpha Particles / Q000009:adverse effects*; D002450:Cell Communication / Q000528:radiation effects; D002460:Cell Line; D018031:Connexin 43 / Q000172:deficiency / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism / Q000528:radiation effects*; D005720:Gamma Rays / Q000009:adverse effects; D017629:Gap Junctions / Q000502:physiology* / Q000528:radiation effects*; D015971:Gene Expression Regulation, Enzymologic / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D005979:Glutathione Peroxidase / Q000235:genetics; D006801:Humans; D018384:Oxidative Stress / Q000528:radiation effects*; D011829:Radiation Dosage; D012867:Skin / Q000166:cytology
chemical_list: D018031:Connexin 43; D005979:Glutathione Peroxidase